Current treatment modalities for heart failure (HF) are aimed largely at late-stage disease, and do not target primary disturbances in the cardiac myocyte. Increasing evidence indicates that derangements in myocardial fuel catabolism and ATP production contribute to the pathological remodeling en route to HF. This renewal proposal builds upon our long-term pursuit of delineating the molecular regulatory mechanisms that control myocardial fuel metabolism and mitochondrial function in the normal and failing heart. Our previous studies have identified a transcriptional regulatory cascade downstream of the inducible transcriptional co-regulators, PPARgamma coactivator 1 (PGC-1) alpha and beta. We demonstrated that PGC-1alpha and beta are necessary for high level of expression of genes involved in cardiac myocyte mitochondrial energy transduction. Studies conducted over the current funding period used both candidate (PGC-1?/-deficient mice) and unbiased molecular profiling strategies to further define the events that are involved in the development of energy metabolic derangements in early stages of heart failure in mice. The results of these studies have led us to hypothesize that the adult mammalian heart is capable of remarkable energy metabolic plasticity in the context of chronic pathophysiological stress such as pressure overload. In support of this hypothesis, we have identified two new gene regulatory pathways that function independent of PGC-1 signaling to control cardiac myocyte energy utilization pathways in the context of mitochondrial dysfunction, such as occurs in the failing heart. The first candidate is the stress-induced nuclear receptor NR4A1 (NUR77). Our preliminary results indicate that NR4A1, and the related factor NR4A3 (NOR1), serve as stress inducible transcriptional regulators of cardiac myocyte glucose utilization. The second candidate is the estrogen-related receptor gamma (ERRgamma). We have found that ERRgamma is capable of inducing the expression of a broad array of genes involved in mitochondrial energy transduction and ATP synthesis. In addition, ERRgamma activates the expression of genes involved in cardiac myocyte differentiation including adult contractile protein genes, a program that could oppose the classic fetal switch of HF. This proposal is designed to test the hypothesis that the adult mammalian heart is capable of adaptive energy metabolic re-programming via gene regulatory pathways downstream of NR4A1 and ERRgamma. In Aim 1, we will further delineate and compare NR4A1 and NR4A3 target genes and pathways in heart. In Aim 2, cardiac gene targets and pathways downstream of the estrogen-related receptor gamma (ERRgamma) will be defined. Aim 3 is designed to explore the roles of NR4A1/NR4A3 and ERRgamma in the normal, hypertrophied, and failing heart using gene-targeted NR4A1/3 or ERRgamma loss-of-function mice. The long-term goal of this project is to identify metabolic modulator therapeutic targets relevant to the treatment of early stage heart failure.